Elvar M. Eyjolfsson1,2, Linn Hege Nilsen1, Daniel Kondziella3, Eiliv Brenner1,2, Asta K. Håberg1, Ursula Sonnewald1
1Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
2St Olavs Hospital, Trondheim, Norway
3Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Tóm tắt
Using a modified MK-801 (dizocilpine) N-methyl-d-aspartic acid (NMDA) receptor hypofunction model for schizophrenia, we analyzed glycolysis, as well as glutamatergic, GABAergic, and monoaminergic neurotransmitter synthesis and degradation. Rats received an injection of MK-801 daily for 6 days and on day 6, they also received an injection of [1-13C]glucose. Extracts of frontal cortex (FCX), parietal and temporal cortex (PTCX), thalamus, striatum, nucleus accumbens (NAc), and hippocampus were analyzed using 13C nuclear magnetic resonance spectroscopy, high-performance liquid chromatography, and gas chromatography—mass spectrometry. A pronounced reduction in glycolysis was found only in PTCX, in which 13C labeling of glucose, lactate, and alanine was decreased. 13C enrichment in lactate, however, was reduced in all areas investigated. The largest reductions in glutamate labeling were detected in FCX and PTCX, whereas in hippocampus, striatum, and Nac, 13C labeling of glutamate was only slightly but significantly reduced. The thalamus was the only region with unaffected glutamate labeling. γ-Aminobutyric acid (GABA) labeling was reduced in all areas, but most significantly in FCX. Glutamine and aspartate labeling was unchanged. Mitochondrial metabolites were also affected. Fumarate labeling was reduced in FCX and thalamus, whereas malate labeling was reduced in FCX, PTCX, striatum, and NAc. Dopamine turnover was decreased in FCX and thalamus, whereas that of serotonin was unchanged in all regions. In conclusion, neurotransmitter metabolism in the cortico—striato—thalamo—cortical loop is severely impaired in the MK-801 (dizocilpine) NMDA receptor hypofunction animal model for schizophrenia.
